Drug Information

Drug (ID: DG00072) and It's Reported Resistant Information
Name
Dabrafenib
Synonyms
1195765-45-7; Dabrafenib (GSK2118436); Tafinlar; GSK2118436A; UNII-QGP4HA4G1B; GSK 2118436; QGP4HA4G1B; N-(3-(5-(2-aminopyrimidin-4-yl)-2-tert-butylthiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide; CHEBI:75045; N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide; N-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; GSK-2118436A; Dabrafenib [USAN:INN]; GSK2118436
    Click to Show/Hide
Indication
In total 1 Indication(s)
Melanoma [ICD-11: 2C30]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[2]
Target Serine/threonine-protein kinase B-raf (BRAF) BRAF_HUMAN [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C23H20F3N5O2S2
IsoSMILES
CC(C)(C)C1=NC(=C(S1)C2=NC(=NC=C2)N)C3=C(C(=CC=C3)NS(=O)(=O)C4=C(C=CC=C4F)F)F
InChI
1S/C23H20F3N5O2S2/c1-23(2,3)21-30-18(19(34-21)16-10-11-28-22(27)29-16)12-6-4-9-15(17(12)26)31-35(32,33)20-13(24)7-5-8-14(20)25/h4-11,31H,1-3H3,(H2,27,28,29)
InChIKey
BFSMGDJOXZAERB-UHFFFAOYSA-N
PubChem CID
44462760
ChEBI ID
CHEBI:75045
TTD Drug ID
D05ROI
VARIDT ID
DR00164
DrugBank ID
DB08912
Type(s) of Resistant Mechanism of This Drug
  RTDM: Regulation by the Disease Microenvironment
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Key Molecule: hsa-miR-126-3p [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
Key Molecule: Vascular endothelial growth factor A (VEGFA) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Myeloma cell metalloproteinase (ADAM9) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
Cell proliferation Activation hsa05200
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTT assay; Flow cytometry assay
Mechanism Description miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A.
Key Molecule: GTPase KRas (KRAS) [3]
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase KRas (KRAS) [3]
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase KRas (KRAS) [3]
Molecule Alteration Missense mutation
p.G12C
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vitro Model Melanoma cells Skin Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description K-RAS mutations (G12C, G12R, Q61H) have been detected in resistant melanoma cell lines and in up to 7% of BRAF inhibitor-treated patients, although kRAS mutations are far less common in primary melanomas than NRAS mutations.
Key Molecule: GTPase Nras (NRAS) [2], [3], [4]
Molecule Alteration Missense mutation
p.Q61K
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Sanger sequencing assay; Next generation assay; Single PCR-based analysis
Experiment for
Drug Resistance		 Progression-free and post-progression survival asaay; Computed tomography assay; Positron emission tomography assay
Mechanism Description Another post-relapse tumor harbored an acquired NRASQ61k missense mutation together with focal BRAF amplification. The resistant tumor from a third patient harbored both a MEk2 mutation and BRAF amplification. Resistance mechanisms are identified in 9/11 progressing tumours and MAPk reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEk2. Our data confirming that MEk2C125S, but not the synonymous MEk1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEk2 mutations in combination therapy-resistant melanomas.
Key Molecule: GTPase Nras (NRAS) [3], [5]
Molecule Alteration Missense mutation
p.Q61R
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Next generation assay; Single PCR-based analysis
Experiment for
Drug Resistance		 Computed tomography assay; Positron emission tomography assay; Progression-free and overall survival assay
Mechanism Description NRAS mutations (Q61R and Q61k in codon 61) were detected in two of ten patients (20%). Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]
Molecule Alteration Missense mutation
p.N126D
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole Exome Sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [2]
Molecule Alteration Missense mutation
p.L46F
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Whole Exome Sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description We identified four mutations involving the MAP2k2 gene (which encodes the MEk2 kinase) in drug-resistant melanoma specimens. Like its homologue MEk1, MEk2 is situated immediately downstream of RAF proteins in the MAPk pathway.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [6]
Molecule Alteration Missense mutation
p.C125S
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Activation hsa04010
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description One portion of the tumour screened by capillary sequencing of reverse transcription PCR (RT-PCR) products contained both the MEk1G128D and MEk2C125S mutations and demonstrated MAPk reactivation.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [7]
Molecule Alteration Missense mutation
p.Q60P
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description Recent whole-exome and RNA sequencing studies have identified a wide array of acquired mutations that confer resistance, including those that reactivate the MAPk pathway (NRAS, kRAS, and MEk1/2 mutations, NF1 loss, BRAF amplification, and BRAF splice variants) and those that activate the PI3k pathway (PIk3CA, PIk3R1, and AkT1/2 mutations and PTEN loss). Of the 6 samples with putative resistance-conferring alterations, 15C harbored an acquired missense PTENR159S mutation in the phosphatase domain, 25C harbored a known acquired MEkQ60L mutation.
Key Molecule: GTPase Nras (NRAS) [3]
Molecule Alteration Missense mutation
p.Q61L
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [3]
Molecule Alteration Missense mutation
p.G13R
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [3]
Molecule Alteration Missense mutation
p.G12R
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy.
Key Molecule: GTPase Nras (NRAS) [3], [6]
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PI3K/AKT/PTEN signaling pathway Inhibition hsa04151
Experiment for
Molecule Alteration		 Whole-exome sequencing assay
Experiment for
Drug Resistance		 Progression-free and overall survival assay
Mechanism Description Somatic mutations in NRAS (Q61k/R/L, G12D/R and G13R) were detected till date by whole exome sequencing in 8-18% of BRAF inhibitor-resistant patients; in most cases, as a late event beyond 12 weeks of therapy. The Prog that did not show evidence of MAPk reactivation by GSEA had two identified resistance mechanisms (MEk2E207k and NRASG12D), but both variants occurred at low frequency (13 and 15% allelic frequency, respectively, by whole-exome sequencing), suggesting heterogeneity within the Prog metastasis.
Key Molecule: MAPK/ERK kinase 2 (MEK2) [6]
Molecule Alteration Missense mutation
p.E207K
 Molecule Info 
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Sanger sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description The Prog that did not show evidence of MAPk reactivation by GSEA had two identified resistance mechanisms (MEk2E207k and NRASG12D), but both variants occurred at low frequency (13 and 15% allelic frequency, respectively, by whole-exome sequencing), suggesting heterogeneity within the Prog metastasis.
References
Ref 1 miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A. J Exp Clin Cancer Res. 2019 Jun 21;38(1):272. doi: 10.1186/s13046-019-1238-4.
Ref 2 The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014 Jan;4(1):94-109. doi: 10.1158/2159-8290.CD-13-0617. Epub 2013 Nov 21.
Ref 3 Tumor heterogeneity and plasticity as elusive drivers for resistance to MAPK pathway inhibition in melanoma. Oncogene. 2015 Jun 4;34(23):2951-7. doi: 10.1038/onc.2014.249. Epub 2014 Aug 11.
Ref 4 BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014 Apr 1;20(7):1965-77. doi: 10.1158/1078-0432.CCR-13-3122. Epub 2014 Jan 24.
Ref 5 Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance. BMC Cancer. 2015 Feb 18;15:61. doi: 10.1186/s12885-015-1029-z.
Ref 6 Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014 Dec 2;5:5694. doi: 10.1038/ncomms6694.
Ref 7 Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma. J Clin Invest. 2015 Apr;125(4):1459-70. doi: 10.1172/JCI78954. Epub 2015 Feb 23.

If you find any error in data or bug in web service, please kindly report it to Dr. Sun and Dr. Zhang.